Coronary disease is one of the most prevalent diseases caused by coronary stenosis or obstruction. It can result in angina pectoris, arrhythmias, myocardial ischemia or infarct and heart failure. Myocardium injury also occurs during reperfusion when the obstructed coronary are suddenly reopened by clinic procedures such as coronary angioplasty, stent or thrombolytic therapy. Reperfusion can results in serious arrhythmias and cardiac failure. A number of drugs have been developed for treating myocardium injury or arrhythmia caused by ischemia or reperfusion. However, the therapeutic benefits of these drugs are limited due to either toxicity or poor efficacy.
Brain stroke including either ischemic stroke or hemorrhagic stroke is one of the leading causes of death in US. It can lead to neuronal injury and cerebral dysfunction as results of ischemia and hypoxia. Brain ischemia may also occur during head trauma or hemorrhagic shock. Since the metabolite rate and oxygen consumption are much higher in brain and central nerve system comparing to other issues, they are more susceptible to ischemia or hypoxia, which may lead to death or irreversible injury. It is desirable to find better medicine to protect against cerebral ischemic injury and preserve brain function.
Compounds of nature origin have been proved to be efficacious and less toxic. For instance, nature digitalis glycoside now plays important roles in treating heart failure and arrhythmia. It has to be used with great caution, however, because the toxic dose of digitalis is very close to its therapeutic dose. To further improve the drug therapy in treating of coronary disease, arrhythmia, heart failure and cerebral stroke, an important approach is discovery more desirable drug from nature source.
Kaurene compounds of formula (I) have been widely studied for their possible biological and pharmacological effects. Most of the studies in art concern their roles in metabolite mechanism. (Kinghorn, A D. 2002, Stevia, by Taylor & Francis Inc.) For instance, it was reported that the said compounds affects cellular metabolite, glucose absorption in intestine and carbohydrate metabolism, energy metabolism in mitochondria of hepatic cells, and metabolite of carbohydrate and oxygen in renal cells. It was also reported that the said compounds cause vasodilation and hypotension. However, the effects of said compounds on cardiac function received litter attention. No study in art has documented the effects of said compounds on cardiac and cerebral ischemia or arrhythmia and myocardium contractility.

wherein                ii. R1: hydrogen, hydroxyl or alkoxy        iii. R2: carboxyl, carboxylate, acyl halides, aldehyde, methylhydroxyl, and ester, acylamide, acyl or ether group hydrolysable to carboxyl.        iv. R3, R4, R5, R6, R8: independently, hydrogen, oxygen, hydroxyl, methylhydroxyl, and ester or alkyloxymethyl group hydrolysable to methylhydroxyl        v. R7: methyl, hydroxyl, and ester or alkyloxymethyl hydrolysable to methylhydroxyl,        vi. R9: methylene or oxygen.        
Natural stevioside has a kaurene skeleton as aglycone; it has a sweetening potency 300 times that of sucrose and has long been used as food sweetener in many countries. It has been shown that stevioside can lowering blood sugar (Gregersen S et al., 2004) and lowering blood pressure (Chen P at el., 2000), but has no effects on heart rate and other parameters related to cardiac function (Hseih M H et al., 2003). In animal studies, it has been shown that stevioside is diuretic, stimulating the secretion of insulin (Jeppesen P B, 2000) and inhibition of energy metabolite in mitochondria (WHO, 1999). However, the possible role of stevioside on cardiac or cerebral ischemia has not been reported previously.
Two well-known kaurene compounds related to stevioside are compound A (as shown in formula (II)) and compound B (as shown in formula (III)).

As aglycone of stevioside, compound B has received great attention and its biological and pharmacological effects have been reported from various animal studies. These includes stimulating the secretion of insulin, inhibiting the absorption, transport, metabolite of carbohydrates, inhibiting energy metabolite (Jeppesen b P, 2000); and inhibiting tubular transport of some xenobiotics and facilitating the excretion of sodium and water in renal. (Chatsudthipong et al., 2001). It was also shown that compound B has certain mutagenic effects (Puzzuto J M et al 1984). However, in the prior art, no study has reported of any effects of compound B on normal cardiac function or of any therapeutic effects on cardiac ischemia and reperfusion injury, arrhythmia, and brain stroke. Compound B can not be catalyzed and cleaved from stevioside by peptic enzymes, but may be by the action of bacteria in animal intestine, then be absorbed. Stevioside can not be metabolized into compound B or A when administered by intravenous injection. Therefore, Results obtained from stevioside studies may not useful in interpreting the effects of its aglycone, i.e. compound B or compound A.
Compound A and compound B have relatively low bio-toxicity. For compound A, the minimum oral lethal dose is 5060 mg/kg in mice and 3160 mg/kg in rats, the median lethal dose (LD50) by intravenous injection is 503 mg/kg in rats. The major symptoms of toxicity at lethal dose are vasodilation and renal failure (Zhongguo et al., 1994). For compound B, the oral median lethal dose (LD50) is 1500 mg/kg in rats (WHO, 1999). Compound A and compound B is relatively safe comparing with common drugs according to the lethal doses.
To our knowledge in art, compound A and compound B have not been used in pharmaceutical compositions for therapeutic use.
In short, coronary disease and brain stroke pose a serious threat to human health. Although drugs of natural origin available are efficacious in treating these diseases, for instance digitalis, but their clinic benefits are limited due to toxicity, Kaurene compounds of formula (I) represent a class of natural compounds, some of which have subjected to a widely studies as a sweetener and revealed a good safety profile. However, the possible therapeutic roles of kaurene compounds on coronary disease or brain stroke have not been determined previously. To overcome the shortcomings, in the invention we have first determined and reported the therapeutic use of kaurene compounds of formula (I) and its preferred compounds in treatment of cardiac and cerebral ischemic diseases by utilizing well-characterized rat models and by more specifically and thoroughly screening and testing.